When Steven Benner set out to re-engineer genetic molecules, he didn't think much of DNA. "The first thing you realize is that it is a stupid design," says Benner, a biological chemist at the Foundation for Applied Molecular Evolution in Gainesville, Florida. (Emphasis added.)

Well, at least he said it was a design. The subtitle of Roberta Kwok's article states, "DNA has been around for billions of years -- but that doesn't mean scientists can't make it better." The DNA Design Challenge is on!

Contestant Benner (pictured at right) begins with the familiar strategy of intimidating the opponent:

"You're trusting your valuable genetic inheritance that you're sending on to your children to hydrogen bonds in water?" says Benner. "If you were a chemist setting out to design this thing, you wouldn't do it this way at all."

Note how he seems to allow the possibility that it was designed. The bluffing ends abruptly, though, when Benner admits that improving on natural DNA is not easy.

Life may have had good reasons for settling on this structure, but that hasn't stopped Benner and others from trying to change it. Over the past few decades, they have tinkered with DNA's basic building blocks and developed a menagerie of exotic letters beyond A, T, C and G that can partner up and be copied in similar ways. But the work has presented "one goddamn problem after another," says Benner. So far, only a few of these unnatural base pairs can be inserted into DNA consecutively, and cells are still not able to fully adopt the foreign biochemistry.

Kwok speculates about possible applications of this research into designed DNA -- unnatural DNA with alternative base pairs, alternative sugars, and alternative ways of joining them together. Even without spinoff technologies, "the sheer novelty of it all" motivates researchers like Benner to tinker with its design, seeing if engineered organisms could work with it.

In creating these life forms, researchers could learn more about the fundamental constraints on the structure of genetic molecules and determine whether the natural bases are necessary for life or simply one solution of many.

Since all earth life uses the DNA we are familiar with, a question remains whether alternatives could be viable. Gerald Joyce, another origin-of-life researcher at Scripps Research Institute, thinks so: "Earth has done it a certain way in its biology... But in principle there are other ways to achieve those ends."

Natural DNA was in the lead in 1986 when we find Benner tinkering with the sugar-phosphate backbone:

He quickly realized that what seemed like a flaw might be a feature. When he and his team replaced the backbone's negatively charged phosphates with neutral chemical groups, they found that any strand longer than about a dozen units folded up on itself -- probably because repelling charges were needed to keep the molecule stretched out.

Benner and others have had more luck toying with the bases on the backbone. "The base pairing, which is at the center of genetics, turned out to be for us the most malleable part of the molecule," he said. Researchers have succeeded in swapping natural bases for artificial ones. They even got RNA polymerase, the transcribing machine, to read some of them. Apparently wrong keys can sometimes fit the lock if they are similar enough.

This has started a rush of "base jumping" experiments with unnatural bases. Floyd Romesburg at Scripps experimented with 3,600 combinations of 60 bases for the pair that copied the most efficiently and accurately. Two winners "walk a thin line" between being hydrophobic and hydrophilic at key positions, Kwok wrote.

A major challenge remained, however: researchers had to show that DNA would retain the unnatural base pairs while billions of copies are made. If enzymes pair unnatural with natural bases too often, the new letters could eventually disappear.

Various teams have achieved remarkable success with the unnatural bases, measuring up to 99.99% accuracy in copying. Their rates are now "overlapping with the sloppiest rate for natural DNA." Romesburg put it, "Our best case is now approaching nature's worst case."

Impressive, but natural DNA still is in the lead. Now, another hurdle: tweaking the transcription machine:

Unnatural bases still have a lot to prove, however. Researchers haven't shown that polymerases can copy more than four of the paired bases in a row. The polymerase is "the hard nut to crack", says Benner. And the solution may be to re-engineer it, too.

A Cambridge team led by Phillip Holliger built an alternative genetic molecule called XNA, then built a polymerase through directed evolution of natural polymerase to come up with a design that could transcribe it. "Much of the tinkering so far has been done in vitro," Kwok writes, "but researchers hope to show that organisms can read and process the information."

Benner, Romesberg and Hirao are also working to coax cells to accept their base pairs. But even if the cells accept the pairs, they might have trouble carrying out processes such as recombination -- a highly orchestrated reshuffling of genetic material. "It's not just a matter of getting these darn things in," says Andrew Ellington, a biochemist at the University of Texas at Austin and a former graduate student of Benner. "I think this is going to be a modestly Herculean task from here on out."

Kwok leaves the human engineers at this impasse, with Benner complaining that he can't yet get the unnatural bases on an alternative backbone in one organism simultaneously. "Our theory is not good enough for us to go in and do both at the same time," he said. Natural cells make it look so easy!

From there, the article veers off into practical applications like drug design that might come from this research. But the motivation remains to see if humans can improve on life's code. Eric Kool, now at Stanford, feels it:

Practical applications aside, researchers are still driven by what Kool calls the "science-fiction appeal" of designing or even improving on living systems. Earth's early life forms may have settled on their genetic alphabet simply because they were constrained by the chemicals available. Adenine, for example, is easy to make from hydrogen cyanide, which was probably present when life first emerged. Once organisms had a working set of bases, perhaps they got locked into that system. "If you start dabbling too much with your fundamental biochemistry, you're going to get eaten," says Benner. Although RNA -- generally thought to have preceded DNA -- might not be the best possible solution for supporting life, it might be the best solution that could have emerged on prebiotic Earth, Benner suggests.

Kwok allowed Benner to speculate about alternative bases on other planets, but that's all it is so far: speculation. Does life use DNA because it's the only possible answer? "I believe the answer to that question is no," Kool thinks. "And the only way to prove it conclusively is to do it."

Near the end of the article, Kwok reveals some back-pedaling by Benner, who had called DNA a stupid design, and by Holliger who directed evolution (by intelligent design):

So if nucleic acids arose independently on another planet, would they have the same bases? Benner thinks not, unless the organisms were subjected to the same constraints. Some universal rules might apply, however. For example, Benner says that backbones with repeating charges -- which initially seemed to him like a liability -- actually discourage folding and ensure that strands with different base sequences behave similarly during processes such as replication. Although some researchers have had success with alternative backbones, many attempts have resulted in molecules that are too stiff or too loose to form a helix. "I think there is a limit to the chemical variation that can be introduced," says Holliger.

It seems premature, therefore, for Benner to call DNA a stupid design. "Stupid is as stupid does," Forrest Gump's mother taught him. If by applying all his intelligent efforts for decades he cannot improve on natural DNA, with its "highly orchestrated" processes and exceptional fidelity, he is not scoring anywhere near as well as the thing he calls stupid.

What if these researchers do succeed some day in improving on life's code? Would it support the case for materialism? No. The obvious inference would be that it came about through the concentrated efforts of numerous intelligent agents over many years. It would also be a backhanded compliment to natural DNA for motivating them to work so hard to reverse-engineer it.

Intelligent design theory does not require a design to be absolutely perfect: just designed. Many natural and artificial designs exhibit "constrained optimality," where parts have to work together against competing interests. Discovery Institute's Jay Richards uses the example of a laptop computer. You don't want the largest monitor, the biggest hard disk, and the fastest processor when you want a product that can fit in a shoulder bag or sit on a lap without starting the user's clothes on fire. You want the best all-around design -- something that hits the "sweet spot" between competing design goals.

That's exactly the kind of optimal design seen in DNA. It's also cool to speculate that other designs are possible. If so, it would mean DNA is "contingent" -- one good design out of other possibilities. In other words, nature was not forced to converge on DNA; it was a choice. ID would not take a hit whether the backbone and base pairing were by necessity or contingent. The genetic code itself, though -- the sequence of bases, and their meaning -- certainly is contingent.

The Nature article begins with bluff and bluster about what a poor design DNA was, and how researchers could improve on it. By the end, the research team seems reluctantly admiring of their natural competitor. Don't expect them to surpass it any time soon -- especially if they leave off their intelligent efforts and resort to natural selection.